Trilogy of drug repurposing for developing cancer and chemotherapy-induced heart failure co-therapy agent  

作　　者：Xin Chen Xianggang Mu Lele Ding Xi Wang Fei Mao Jinlian Wei Qian Liu Yixiang Xu Shuaishuai Ni Lijun Jia Jian Li 

机构地区：[1]State Key Laboratory of Bioreactor Engineering,Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism,Frontiers Science Center for Materiobiology and Dynamic Chemistry,Shanghai Key Laboratory of New Drug Design,School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China [2]Cancer Institute,Longhua Hospital,Shanghai University of Traditional Chinese Medicine,Shanghai 200032,China [3]College of Pharmacy,Jinan University,Guangzhou 510632,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第2期729-750,共22页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China (Grant Nos. 22177076, 81820108022, 22037002);the Shanghai Frontier Science Center of Optogenetic Techniques for Cell Metabolism (2021 Sci&Tech 03-28, China);Shanghai Frontiers Science Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation (2021KJ03-12, China);the Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZDCX20212702, China);the Chinese Special Fund for State Key Laboratory of Bioreactor Engineering(2060204);Innovation Program of Shanghai Municipal Education Commission (2019-01-07-00-10-E00056, 2021-01-07-00-02-E00104, China);the Scientific and Technological Innovation Action Plan of Science and Technology Commission of Shanghai(20JC1411300, China)

摘　　要：Chemotherapy-induced complications,particularly lethal cardiovascular diseases,pose significant challenges for cancer survivors.The intertwined adverse effects,brought by cancer and its complication,further complicate anticancer therapy and lead to diminished clinical outcomes.Simple supplementation of cardioprotective agents falls short in addressing these challenges.Developing bifunctional co-therapy agents provided another potential solution to consolidate the chemotherapy and reduce cardiac events simultaneously.Drug repurposing was naturally endowed with co-therapeutic potential of two indications,implying a unique chance in the development of bi-functional agents.Herein,we further proposed a novel“trilogy of drug repurposing”strategy that comprises function-based,targetfocused,and scaffold-driven repurposing approaches,aiming to systematically elucidate the advantages of repurposed drugs in rationally developing bi-functional agent.Through function-based repurposing,a cardioprotective agent,carvedilol(CAR),was identified as a potential neddylation inhibitor to suppress lung cancer growth.Employing target-focused SAR studies and scaffold-driven drug design,we synthesized 44 CAR derivatives to achieve a balance between anticancer and cardioprotection.Remarkably,optimal derivative 43 displayed promising bi-functional effects,especially in various self-established heart failure mice models with and without tumor-bearing.Collectively,the present study validated the practicability of the“trilogy of drug repurposing”strategy in the development of bi-functional cotherapy agents.

关 键 词：ANTICANCER Heartfailure COMPLICATION Drug repurposing Bi-functional drug 

分 类 号：R96[医药卫生—药理学]